Co-director, Jane and John Justin Neurosciences Center, Cook Children’s Hospital

M. Scott Perry, MD

"We have resources on there. We’re also linking out to the Epilepsy Foundation’s resources as well as specific resources just for the very severe cases.”

As a way to raise awareness of the importance of seizure action plans (SAPs), the Dravet Syndrome Foundation, Lennox-Gastaut Syndrome (LGS) Foundation, and Tuberous Sclerosis Alliance came together to launch the inaugural SAP Awareness Week, an initiative that was held from February 8 to 15, 2021. The collaboration of the 3 advocacy organizations, titled the SAP Coalition, featured a social media campaign and new website designed to highlight the need for these plans for patients with epilepsy, especially should an emergency occur.

In efforts to continue these ongoing conversations, 

 hosted a roundtable discussion with multiple notable leaders within the epilepsy community. Scott Perry, MD, co-director, Jane and John Justin Neurosciences Center, Cook Children’s Hospital; Orrin Devinksy, MD, director, Comprehensive Epilepsy Center, NYU Langone; and Tracy Salazar, PhD, executive director, LGS Foundation, all participated in the multi-segment conversation.

In this fifth segment, Salazar gives her thoughts on the benefits of utilizing an advocacy organization as a resource when constructing or updating an SAP. She also details how their role can be crucial for both a parent and patient perspective.

Videos

A roundtable discussion featuring Scott Perry, MD, Orrin Devinsky, MD, and Tracy Salazar, PhD, details how advocacy organizations can help guide patients with epilepsy and their caregivers with a seizure action plan.

Role of Advocacy Organizations in Seizure Action Plans, Seizure Education

"Things change. A seizure action play is not something that you are required to visit only once a year. Seizure patterns change. Seizure types, seizure frequencies change. It is important to see your provider if these sorts of things change.”

The differences in seizure action plans (SAPs) for children as compared to adults with epilepsy can be staggering. Oftentimes children will have their SAP developed shortly after birth and must maintain and update them as a requirement for parts of schooling. Children can struggle with fully understanding their condition, how their seizures can evolve, and what to do during an emergency setting.

For adults, though, they may have left their parents for a job or educational reasons and now live alone. The lack of resources or caregivers at the disposal for adult with epilepsy can definitely raise the need for a more constructed SAP, according to Orrin Devinsky, MD. Devinsky, the director of the Comprehensive Epilepsy Center at NYU Langone, along with other epilepsy specialists, feel as though the important question when developing an SAP is “who is around?”

In efforts to raise awareness about SAPs as part of the inaugural SAP Awareness Week, 

hosted a roundtable discussion that included Devinsky, along with Scott Perry, MD, co-director, Jane and John Justin Neurosciences Center, Cook Children’s Hospital, and Tracy Salazar, PhD, executive director, Lennox-Gastaut Syndrome (LGS) Foundation.

In the fourth segment, the panel discussed the differences in seizure action plans as a child enters adulthood, the need for constant adjusting and monitoring, and why the resources around a patient with epilepsy will help tailor their SAP going forward.



A roundtable discussion featuring Scott Perry, MD, Orrin Devinsky, MD, and Tracy Salazar, PhD, details how seizure action plans change from pediatrics to adults and the need for adjustments.

Adjusting Seizure Action Plans With Age

"Certain conditions are more prone to go into status epilepticus or other types of emergencies. Obviously, Lennox-Gastaut [syndrome] is a great example. Dravet syndrome is another fine example.”

Epilepsy isn’t a single disease or condition. There are many types of epilepsy with different symptoms and patterns. Within these epileptic groups, there is also a range of seizure types, the frequency in which they occur, and the methods in which they are treated. Some epileptic types are considered more severe and can encounter a greater number of seizures or require a certain number of rescue medications compared to others.

With that in mind, from a caregiver perspective, developing and tailoring a seizure action plan (SAP) to an given patient with epilepsy may lead to better response when seizures occur and even more situational awareness on whether to refer to paramedics.

As part of SAP Awareness Week, February 8 to 15, 2021, 

 hosted a roundtable discussion with multiple leaders within the epilepsy community. Scott Perry, MD, co-director, Jane and John Justin Neurosciences Center, Cook Children’s Hospital; Orrin Devinksy, MD, director, Comprehensive Epilepsy Center, NYU Langone; and Tracy Salazar, PhD, executive director, Lennox-Gastaut Syndrome Foundation, all participated in the multi-segment conversation.

The third segment of this discussion deals with how SAPs can vary across epilepsy types, and why even patients without epilepsy should understand what do to do if someone around them is having a seizure.

A roundtable discussion featuring Scott Perry, MD, Orrin Devinsky, MD, and Tracy Salazar, PhD, details the way seizure action plans can differ depending on seizure phenotype and frequency of seizures.

Differentiating Seizure Action Plans by Epilepsy Type

"Adults should know, and more importantly, the people around them should know what to do.”

In a recent study, only 30% of adult patients with epilepsy responded that they have a seizure action plan (SAP), and only 45% of pediatric patients had an SAP. While adults with epilepsy will have very differently developed SAPs than pediatric patients, the importance of maintaining and adjusting an SAP as a patient gets older is still critical.

Developing an SAP can provide clarification on patient and caregiver concerns, such as understanding what to do during a seizure, when watchful waiting is appropriate, when to intervene with at-home rescue medication, when to call 911 or go to the hospital, and much more. For adults with epilepsy, they may have moved away from their parents and are now responsible for their own actions with no caregiver around them.

As part of SAP Awareness Week, February 8 to 15, 2021, 

 hosted a roundtable discussion with multiple leaders within the epilepsy community. Scott Perry, MD, co-director, Jane and John Justin Neurosciences Center, Cook Children’s Hospital; Orrin Devinksy, MD, director, Comprehensive Epilepsy Center, NYU Langone; and Tracy Salazar, PhD, executive director, LGS Foundation, all participated in the multi-segment conversation.

The second segment of the discussion is centered around the need to improve SAP rates among adults with epilepsy, and why the importance of them does not deteriorate as a patient gets older.

A roundtable discussion featuring Scott Perry, MD, Orrin Devinsky, MD, and Tracy Salazar, PhD, covers the staggeringly low percentage of adults with epilepsy who have seizure action plans.

Improving the Rates of Seizure Action Plan Usage in Adults With Epilepsy

"Every kid is different. What needs action for every kid is different. Understanding for that individual, what is an emergency situation, what is different for their epilepsy and what needs intervention is really important. That’s another thing that seizure action plans bring.”

The inaugural Seizure Action Plan (SAP) Awareness Week, February 8 to 15, 2021, is an initiative to raise awareness about the importance of developing SAPs for patients with epilepsy and their caregivers. Organized by the SAP Coalition, which is a collaboration of the Dravet Syndrome Foundation, the Lennox-Gastaut Syndrome (LGS) Foundation, and the Tuberous Sclerosis Alliance, the initiative features a social media campaign and new website designed to highlight the need for these plans, especially should an emergency occur.

In efforts to continue these ongoing conversations, 

 hosted a roundtable discussion with multiple notable leaders within the epilepsy community. Scott Perry, MD, co-director, Jane and John Justin Neurosciences Center, Cook Children’s Hospital; Orrin Devinksy, MD, director, Comprehensive Epilepsy Center, NYU Langone; and Tracy Salazar, PhD, executive director, LGS Foundation, all participated in the multi-segment conversation.

In this first segment, the 3 rare epilepsy experts give their perspectives on the importance of SAPs and the benefits physicians can derive from developing their own.

A roundtable discussion featuring Scott Perry, MD, Orrin Devinsky, MD, and Tracy Salazar, PhD, covers the logistics behind a seizure action plan and why its necessary to develop one. 

Understanding and Developing a Seizure Action Plan

M. Scott Perry, MD, shares his excitement for future developments and treatments for Dravet syndrome.

M. Scott Perry, MD: The future for Dravet syndrome is really bright, and it’s bright not just for Dravet syndrome, but as a genetic-based epilepsy, it is bright because it is forging the way for other genetic epilepsies, in my opinion. Dravet syndrome is a disease of haploinsufficiency. We all walk around with 2 versions of the SCN1A [gene], and the problem with Dravet syndrome is 1 of them doesn’t work very well, which leaves us with about 50% of the SCN1A protein in those cases. That’s not enough, and thus you have Dravet syndrome.

There are some exciting therapies out there that are really trying to get at the genetic etiology and correct that problem. One is a trial of antisense oligonucleotides [ASOs], which is being investigated by a company called Stoke [Therapeutics]. The SCN1A messenger RNA may come with basically information called a decay exon. If that decay exon is there, even if it’s a good copy of SCN1A, it will be destroyed, and the protein will not be made. The concept here is that by giving a patient with Dravet this antisense oligonucleotide through a spinal tap, the antisense oligonucleotide is a piece of genetic material, basically, that binds to that decay exon and turns it off, and if it turns it off, then this version can get through and be made all the way to a healthy protein. 

So when you only have 1 copy that is working, and some of that working copy gets destroyed just naturally, if you can save it and keep it from getting destroyed, you’ll elevate the amount of appropriately functioning sodium channel, or SCN1A. That’s how that concept works. They’ve shown in a mouse model that it works. It reduced significantly the rate of sudden unexpected death in mice with Dravet syndrome that were given this treatment. They’ve also shown some early evidence that there are decreased seizures in those mice models as well. 

Now, a second approach is one using viral vector therapy. This uses an attenuated adenoviral vector, which is somewhat of a similar approach in that it is, again, a piece of genetic material being injected, in this case intraventricularly, directly into the brain, delivering this payload that will increase the amount of healthy SCN1A. The difference here is that’s more of a DNA approach versus a messenger RNA approach.

Key differences between the two are potentially ASO therapies may need to be given multiple times to be effective because they get broken down over time and you may need to dose it again, whereas a viral therapy is thought to be a one-time thing. Obviously, there’s a difference between an intraventricular injection and a spinal tap, so there are some differences in how it’s administered. Potentially there are some safety differences that we won’t know until those trials are done.

The ASO therapy is in investigation now. Those trials are open and being done. The viral vector therapy is in planning. Hopefully in the coming year that will be done. Along with these 2 approaches, there are some what we call natural history studies. They’re not necessarily natural history studies, but they’re trying to see what the course of this condition is because Dravet syndrome—we’ve talked a lot about seizures, but it’s more than just seizures.

It is cognitive delays. It is problems with sleep. It is problems with behavior. These children will develop difficulties walking as they get older. There are a variety of comorbidities. What we don’t understand is how much of that is inherent to the actual mutation itself and the SCN1A channel, how much of it is the seizures themselves, and if we got control of the seizures, how would that change the comorbidities? And how much of is it the ways we treat the condition to start with? 

These natural history studies are basically following children over time to understand how all of these comorbidities relate to each other so that when we do look at these things like ASO and viral vector therapy, which are disease modifying therapies, we can show that the treatment actually modifies the disease. It doesn’t just change seizure frequency but modifies what happens. The endgame hope is that not only can we find a treatment that stops the progression of the disorder, makes the seizures get better, maybe reverses some of the problems, but what if we had a way to treat this before the condition really even manifests?

If you had newborn screening, and you knew a person carried an SCN1A pathogenic variant, and they started to show the early signs of this condition with seizures, could you treat so early on that you could keep it from progressing at all? That’s really the ultimate goal, to prevent it from happening at all. I honestly think that’s where we’re headed. I do think the future is really bright, and if we can do that for this condition, there are multiple other epilepsies that have genetic pathologies that we may be able to correct as well.

For a community neurologist out there, the advice I give is first of all, just be aware of it. I cannot stress how important that is. Be aware of the condition. Look for those kids who come in with what seems like an atypical febrile seizure. If it’s long, especially if it’s hemiclonic, if they’re seizing every single time they have a fever, be aware of it. Make use of these programs that allow for free genetic testing, but also understand that genetic testing comes with results. 

When you get those results, sometimes they may be hard to interpret because there may be multiple genes that have variance, and not all variance causes disease. Understand that having an SCN1A variant doesn’t necessarily equal having Dravet syndrome, and having Dravet syndrome doesn’t necessarily equal having an SCN1A variant. Just be aware of that. There are multiple centers across the country that specialize in not only genetic epilepsy, like mine, but specialize particularly in Dravet syndrome. 

You can go to the Dravet Syndrome Foundation, where they have a list of sites that are very familiar with this condition. We’d be happy to help you out if you have any questions, you can always contact any of us. Many of us serve on the scientific advisory board or the medical advisory board and are happy to help other physicians care for this. Really, it’s making the diagnosis, being aware of it, and just getting the kid to the right types of treatments early on. That’s probably the best advice I can give to community neurologists.

Future Outlook for Dravet Syndrome

M. Scott Perry, MD, reviews how cannabidiol and fenfluramine are chosen for patients with Dravet syndrome based on concomitant medications and associated adverse events.

: Are there any populations where a cannabidiol might be preferable over fenfluramine? I think in general both medications have good seizure response, so I think it comes down to maybe concomitant medications that the child is on and the adverse effects associated with it. If you’ve got a child who maybe is already on clobazam or valproic, you may have a little more risk of somnolence or elevated liver enzymes; maybe you would choose fenfluramine instead.

If you’ve got a kid who already has issues with feeding, weight has already been a problem, maybe they have preexisting cardiac conditions, maybe you would choose cannabidiol. In my own population, I’ll tell you, the majority of them have probably been on both medications at some point. It’s almost always a matter of trying to find which one, or maybe both together, gives you the best seizure control, but the adverse effects may play a role in which one you choose first when you’re trying to figure that out.

Dosing for the both these medications is fairly simple. The cannabidiol is generally titrated up to about 10 mg/kg per day as a starting target dose. I usually start the first week with around 5 mg/kg per day, divided twice a day, and then up to 10 mg/kg. Then if it’s tolerated, if they’re still having seizures, you can try to go higher, working your way up to 20 mg/kg per day. I generally tell people as I titrate up that as we go up, if we’re not seeing seizure control get any better, there’s probably no need to stay at the higher dose.

We can just come right back down to where we were. If we get some additional efficacy, as long as it’s tolerated, that’s fine. We’ll work our way on up to the higher dose. Same with fenfluramine. The indication and titration schedule for fenfluramine is up 0.7 mg/kg per day. No higher—this is important—no higher than 26 mg per day. There is a limit on how much fenfluramine you give based on weight, and that is if the patient is not on stiripentol. 

If the patient is taking stiripentol, the dose of fenfluramine should be titrated up to 0.4 mg/kg per day, not to exceed a daily dose of 17 mg. The reason for that is there is a higher viability of fenfluramine in the setting of stiripentol, and so the dosing needs to be adjusted. Personally, the way I have had done it, my experience with fenfluramine, is I generally start the dosing at about 0.2 mg/kg per day and work up to around 0.4 to 0.5 mg/kg, see how the child is doing, and then go the rest of the way to 0.7 mg/kg per day if it is necessary. 

I’ve seen a lot of kids who tend to do well in that middle area, and so I don’t need to go all the way up. Fenfluramine is a drug whose concentration is 2.2 mg/mL, so from a mathematic standpoint and ease of use for parents, I try to find doses that are at nice, even, or at 0.5 increments, to make the dose simple for them. I think that’s something people should always think about.

Choosing Cannabidiol or Fenfluramine for Dravet

M. Scott Perry, MD, discusses the exciting approval of cannabidiol and fenfluramine for Dravet syndrome.

: The last couple of years have been really exciting because we’ve actually seen a lot of medications approved specifically for an indication of Dravet syndrome. As I said earlier, stiripentol was approved about 2 years ago based on the data out of Europe. Most recently, 2 new medications have been approved, the first being Epidiolex which is cannabidiol [CBD], as well as fenfluramine or Fintepla. Cannabidiol is a medication whose mechanism of action from an epilepsy standpoint is actually not known.

We know there are 2 receptors—CB1, CB2—that are cannabidiol receptors in the brain, but the CBD itself does not interact on those receptors, so that does not appear to be the mechanism of action. The drug has been approved for the treatment of 3 conditions: Lennox-Gastaut syndrome, Dravet syndrome, and now tuberous sclerosis complex, most recently, treating children ages 1 and up and the seizures associated with those syndromes. 

In the Dravet population specifically, in those phase 3 trials, the average reduction overall of seizures was in the 42%, 45% range in people who took the cannabidiol versus those who took placebo. The placebo rates in those studies was in the mid-20% range, so 22% to 25%, so a higher placebo rate than we do see in some other studies. But nonetheless, significantly, it was an effective drug at a dose of 10 mg/kg per day. Now, there’s a second study where they compared a higher dose, 20 mg/kg per day to 10 mg/kg per day, and both studies showed similar seizure reduction overall, as I said, about 45%, 49%.

There was not a significant improvement in taking the higher dose versus the lower dose, but there was a difference with regard to [adverse] effects. More people had [adverse] effects the higher the dose you went. What kind of [adverse] effects might you get from taking this drug? You see some of the common things we see with other antiseizure medicine, so sleepiness, fatigue, diarrhea is more common. As far as the sleepiness goes, a lot of those patients were also on clobazam, and what’s important is that clobazam, the active metabolite of clobazam, which is desmethylclobazam, elevates as much as 5 times its baseline value in the setting of CBD. 

For that reason, if you have sleepiness with this drug and the patient’s on clobazam, one way to maybe tolerate it better is to reduce the clobazam. That may fix the problem. Another adverse effect that people should be aware of is that there is a risk of elevated liver transaminases when taking CBD, Epidiolex. This tends to occur most often in the setting of also using valproic acid. Again, a lot of these patients are on those drugs, so you just need to be aware of it.

You need to monitor liver function testing when treating. The rate in the studies was anywhere from 7% to 15%. And again, it was much higher in people who took both CBD and valproic acid, so you certainly need to be aware of that. In my experience, the medication, it’s great to have it as another option for these patients. It’s great to have a medication that has had a phase 3 trial to tell you how it works and what to expect. It’s nice to know how it works as far as its interaction with other medications that we commonly encounter.

I think overall the drug is really well tolerated in the population despite the [adverse] effects I’ve listed. It’s actually really well tolerated, and it can be a very effective medication for many kids with Dravet syndrome, so it’s definitely worthwhile to have along. Now, a second drug that came out more recently is fenfluramine, which is branded as Fintepla in the United States. That’s another drug whose mechanism of action honestly is not really known from an epilepsy standpoint. We know that it works on the 5-HT2B [5-hydroxytryptamine receptor 2B] receptor, which is a serotonin mechanism, but that serotonin mechanism does not appear to be where it exerts its antiseizure properties. 

That drug was approved after phase 3 trials in using fenfluramine in 3 groups. We had fenfluramine at 0.7 mg/kg, fenfluramine at 0.2 mg/kg, and then a placebo group in the phase 3 trials. What they saw in that is that patients with Dravet syndrome had an almost 67% to 70% reduction in overall convulsive seizures during the treatment phase compared to the placebo group. That’s comparing the high dose to the placebo group.

The lower dose group also had a significant reduction of seizures, about 30%, so both doses seem to be effective. They looked at a couple of other end points in that particular trial. They looked at 50% and 75% responder rates. Over 50% of the patients had a 50% responder rate, and actually, about 35%, 40% had a 75% reduction in seizures when taking the high dose group. So again, another very effective drug; 25% of the patients in the study either had zero or 1 seizure during the 14 weeks of the trial also, which again, when you think about Dravet syndrome where seizures are quite frequent, that was an impressive outcome overall. 

The drug is well tolerated. It was a drug that in the past had been used as an appetite suppressant for weight loss, and so not surprisingly, one of the adverse effects we saw was decreased appetite when comparing it to placebo. Fortunately, while decreased appetite was present, significant weight loss was generally not present. Some did have it, but in general it was not a huge problem, but something to keep an eye on when treating patients with this drug.

The other thing to be aware of is that in the past, again fenfluramine has been used for other indications, there has been cardiac valvulopathy as well as pulmonary arterial hypertension. As a result, there is a REMS [Risk Evaluation and Mitigation Strategy] program and a requirement to get echocardiograms before using this drug, every 6 months while the patient is on the drug, and then, if they discontinue it, getting that testing done 3 to 6 months after they come off the drug. 

The fortunate thing to know is that with over 3 years now worth of data from the fenfluramine program, and well over a few thousand echocardiograms and a few hundred patients, there have been no episodes of cardiac valvulopathy or pulmonary arterial hypertension. While we are still monitoring it, because now this is a real-world scenario, not under a protocol from a phase 3 trial, we have fortunately not seen that as an adverse effect to be concerned about so far.

Approval of Cannabidiol and Fenfluramine for Dravet

M. Scott Perry, MD, discusses historically approved therapies for the first-, second-, and third-line treatment of Dravet syndrome.

: How can you treat once you know a child has Dravet syndrome? As I said, there are certain treatments that are likely to be more successful. In the past and until just the last couple of years, there was really a triumvirate of medications that we often considered, mostly based on expert opinion, that being clobazam, valproic acid, and stiripentol. Neither clobazam nor valproic acid have had trials specific to Dravet syndrome, but as I said, through expert opinion they were felt to be very effective. 

Both have GABA [gamma aminobutyric acid] mechanisms, so working in the inhibitory system, it made sense they’d be useful for Dravet syndrome. Most of the data we have about them are retrospective reviews of experience with the medication, with responder rates—or greater than 50% reduction—probably around 30% or so for clobazam; some studies report 25% to 50% for valproic acid. Stiripentol is a medication that was really the first to have a placebo-controlled trial specific to Dravet syndrome. 

That was done in Europe, and in those trials, they showed that a reduction of convulsive seizures was on the range of about 69%, 70% in people who took the stiripentol. Importantly, in those trials all the patients were on valproic and clobazam. We know that clobazam levels, for example, elevate in the setting of stiripentol, so there is some play of not just stiripentol as a primary medication, but the elevation of clobazam also likely contributing to some improvement.

As a result, a couple of years ago, stiripentol was approved in the United States for the treatment of Dravet syndrome in children ages 2 and older when used with clobazam. That’s an important thing for people to be aware of, that that is the indication here. There is a variety of other treatments that we would really consider second- and third-line treatments for Dravet syndrome, and basically that field is antiseizure medications that don’t have a sodium channel mechanism of action. 

They’re all fair game. For instance, topiramate is commonly used. I always caution people with the topiramate, while I think it is a good medicine, it does result in decreased sweating and thus increases the risk for overheating, which we already know is a risk factor in this population. It can also, of course, decrease appetite. The ketogenic diet is commonly used. Studies of the ketogenic diet and Dravet show response rates in the range of 40%, 50%, as we see in some other epileptic encephalopathies in that treatment.

Levetiracetam and zonisamide are commonly used. Ethosuximide, as I said, a lot of these kids have absence or atypical absence seizures, so ethosuximide can be very helpful for that specific type. Vagal nerve stimulation has been another nonmedicinal approach that people have used for the treatment of Dravet syndrome with some success.

Treatment Options for Dravet Syndrome

M. Scott Perry, MD, stresses the importance of an early diagnosis for Dravet syndrome, and what tools are available to help with early diagnosis.

: There are a lot of options in making a diagnosis for Dravet syndrome early on, and of course, as I said, the first thing is to have a high index of suspicion for these kids based on how they present. But fortunately, at least in the United States, we have some programs that make it much easier to acquire that genetic testing. For instance, there are some programs like the Behind the Seizure program, which offers free genetic testing, a panel of multiple genes involved in epilepsies that you can get for children under the age of 8 that present with new onset seizures. 

This is a great way to get that testing accomplished to try to see if they have a mutation in SCN1A or, frankly, in any of the other common genes. Once you know that a child has an SCN1A variant that is likely disease-causing, whether the presentation is maybe Dravet syndrome or not right at that point, then that really informs the treatment for you. There are certain drugs you should not use, and those would be drugs where there’s a sodium channel mechanism of action.

You should not use that to treat those kids on a daily basis because it can exacerbate their epilepsy. There are certain medications that may be more favorable for them as there have been 3 medicines just approved in the last couple of years specifically for the diagnosis of Dravet syndrome. It also informs you that there’s certain things you should have the family be aware of. Since we know that these kids can have more seizures in the setting of overheating, then you can make plans to limit that as much as you can.

Here I am in Texas, what kinds of things do we do? We make sure that if they’re outside, they’re taking frequent breaks in the shade, they’ve always got water with them, a cooling fan. A lot of kids wear a cooling vest, different things to keep the temperature down. When they’re getting their vaccinations, you may be treating ahead of time with antipyretics to keep the fever down around that.

You also know with these kids that they have long seizures, so knowing that this child has this condition, be clear that you have a plan not just for the family but for emergency medical personnel in how to treat this child if they have a seizure. What is the rescue plan, what steps need to be taken, and how long do you wait between each step? Because these kids can go into status epilepticus very quickly, it’s important to know that an aggressive therapy is necessary to try to stop that seizure before it gets out of hand.